Studies on the Control of Lipogenesis: Strain Differences in Hepatic Metabolism

Abstract

Detailed studies of hepatic metabolism of lipemic BHE and nonlipemic Wistar rats were conducted. Hepatic lipogenic capacity was varied through the use of starvation or meal feeding. Livers were clamped in precooled copper plates and used for the assay of glycolytic, gluconeogenic, and lipogenic metabolites. Redox and phosphorylation states were calculated. Mitochondrial metabolism was evaluated through studies of the oxygen consumption of isolated mitochondria and through the study of the activities of the alpha-glycerophosphate and malate aspartate shuttles and ATPase. BHE rats have higher phosphorylation states, higher redox ratios, and lower shuttle activities and oxygen consumption by isolated mitochondria than their Wistar cohorts. The differences in oxidative phosphorylation, redox and phosphorylation states, and in the various shuttle activities suggest that BHE liver cells are geared towards lipogenesis at the expense of oxidative phosphorylation. It appears that the activity of the shuttles is controlled in part by phosphorylation state which in turn appears to affect respiration. We theorize from these data that genetically determined differences in the structure and function of the mitochondrial membrane (and perhaps the cell membrane as well) may affect the communication (via metabolites and adenine nucleotides) between the cytosol and mitochondria. Subtle differences in the exchange of metabolites and/or adenine nucleotides across the mitochondrial membrane could thus explain the lipogenic tendency of the liver of the BHE rat and the subsequent development of maturity onset hyperlipemia and hyperglycemia in this strain of rat.

Hyperglycemia-induced mitochondrial alterations in liver

“…The following studies involving BHE rats provide evidence for altered oxidative phosphorylation states, presence of mitochondrial retinoic acid receptors and hence the requirement for higher concentrations of vitamin A which also increases levels of mitochondrial transcription factor A (Berdanier et al 1979;Everts et al 2002). Mitochondrial metabolism was evaluated by measuring oxygen consumption of isolated mitochondria and by studying the activities of the alpha-glycerophosphate and malate aspartate shuttles and ATPase in lipemic BHE and nonlipemic Wistar rats (Berdanier et al 1979).…”

“…The following studies involving BHE rats provide evidence for altered oxidative phosphorylation states, presence of mitochondrial retinoic acid receptors and hence the requirement for higher concentrations of vitamin A which also increases levels of mitochondrial transcription factor A (Berdanier et al 1979;Everts et al 2002). Mitochondrial metabolism was evaluated by measuring oxygen consumption of isolated mitochondria and by studying the activities of the alpha-glycerophosphate and malate aspartate shuttles and ATPase in lipemic BHE and nonlipemic Wistar rats (Berdanier et al 1979). Lipemic BHE rats had higher phosphorylation states, higher redox ratios, and lower shuttle activities and oxygen consumption by isolated mitochondria than their nonlipemic Wistar cohorts and the differences in oxidative phosphorylation, redox and phosphorylation states and in the various shuttle activities suggested that BHE liver cells were geared towards lipogenesis at the expense of oxidative phosphorylation.…”

Mutated ATP synthase induces oxidative stress and impaired insulin secretion in β‐cells of female BHE/cdb rats

“…Consequently, the efficiency of oxidative phosphorylation is compromised [3] and ATP production is reduced [4]. Previous studies established that aged male BHE/cdb rats had abnormal islet morphology, but relatively normal insulin content [5].…”

The Cdb:BHE Rat--A Model for Non-Insulin-Dependent, Nonobese Diabetes Mellitus

“…Tolerance can be influenced by both age and diet. Gestational diabetes (glucose tolerance normal before and after gestation but not during the TABLE 1 Protocols Followed for the Development of the Cdb.BHE Rat Colony last third of gestation) can be shown in 200-day-old female rats if they are fed a 22 percent fat diet, which approximates the composition of the average diet consumed by people in the United States (Berdanier et al, 1979;Bue et al, 1989).…”

“…These values are only slightly higher than what one might anticipate for normal rats of this age. Fasting serum cholesterol values seem to be unaffected by diet composition, whereas, fasting serum triglycerides are elevated sometimes by as much as 50 percent when purified diets containing 5 percent saturated fat and/or 65 percent sucrose are fed (Berdanier et al, 1979;Kim et al, 1989). "Stock diet, Purina Laboratory Animal Chow.…”